The liver is an important organ which has various functions such as metabolic regulation and storage of sugar, protein and lipid which are three major nutrients, and decomposition and detoxification of substances unnecessary to the living body. These functions suffer acute or chronic disorders due to an excessive in take of alcohol, viral infection, bad eating habits, stress, smoking, etc. The advance of these disorders results in diseases such as acute hepatitis, chronic hepatitis, hepatic cirrhosis, alcoholic fatty liver, hepatitis B and liver cancer.
When liver cells are damaged by virus, alcohol, etc., enzymes such as aspartate aminotransferase (glutamic-oxaloacetic transaminase, hereinafter abbreviated as GOT) and alanine aminotransferase (glutamic-pyruvic transaminase, hereinafter abbreviated as GPT) in the cells leak into the blood, which raise the values indicating the activities of these enzymes. Accordingly, the levels of GOT and GPT activities in the blood are known as indices of the levels of the liver function disorders.
Known drugs used for the prevention or treatment of the liver function disorders include antiviral agents such as acyclovir, immunosuppressive agents, glutathione and the like. Foods and drinks which are recognized to be effective for protecting, strengthening and improving the liver functions include for example, turmeric, milk thistle, sesame lignan, oyster extract, liver extract and the like.
However, a strong need consistently exists for the development of pharmaceutical agents which are effective in prevention or treatment of liver diseases, and of health foods and drinks or animal feeds which enable prevention or treatment of hepatopathy by daily intake.
In connection with stilbenoid compounds, anti-allergic activities, anti-oxidative activities and anti-bacterial activities have been conventionally investigated on compounds isolated from Hydrangeae Dulcis Folium which is a herbal medicine [Summary of Lectures at the 2nd Symposium on Medicines and Foods, p. 85, 1999, Nihon Yakuyou Shokuhin Gakkai Zyunbi Iinkai (Japanese Society of Medicated Foods, Preparatory Committee)], and the like.
Reports have been made as follows on in vitro activities of the stilbenoid compounds.
In regard to the anti-allergic activities, it is reported that release of histamine from mast cells induced by compound 48/80 or calcium ionophore A23187 is suppressed by thunberginol A-G (50% inhibitory concentration: 9.4-92 μM), but is not suppressed by phyllodulcin or phyllodulcin 8-O-glucoside, hydrangenol, hydrangenol 8-O-glucoside, hydramacrophyllol A and B at 100 μM [Bioorganic & Medicinal Chemistry, 7, 1445 (1999)].
The extract of Hydrangeae Dulcis Folium (2000 mg/kg) is reported to suppress rat skin passive anaphylaxis through oral administration [Journal of the Pharmaceutical Society of Japan, 114(6), 401 (1994)]. In addition, it is reported that phyllodulcin 8-O-glucoside (300 and 500 mg/kg), hydrangenol (500 mg/kg), hydrangenol 8-O-glucoside (300 and 500 mg/kg), thunberginol A (300 and 500 mg/kg), thunberginol F (300 and 500 mg/kg) suppress rat skin passive anaphylaxis through oral administration, but phyllodulcin (300 and 500 mg/kg) does not suppress rat skin passive anaphylatic reaction [Biological & Pharmaceutical Bulletin, 22(8), 870 (1999)].
In connection with the anti-oxidative activities, it is reported that: as to DPPH (1,1-Diphenyl 2-Picrylhydrazyl) radical capturing capacity, the extract of Hydrangeae Dulcis Folium exhibits 50% capturing action at 0.099 mg, while phyllodulcin exhibits this activity at 0.208 mg, and hydrangenol at 1.074 mg; as to linoleic acid oxidation (iron rhodanate method), phyllodulcin exhibits more potent suppressive activity than α-tocopherol or BHA (Butylated Hydroxyanisole), while hydrangenol exhibits a weak suppressive activity thereto; and as to NADP (Nicotinamide Adenine Dinucleotide Phosphate) H dependent lipid peroxidation in rat liver microsome, phyllodulcin exhibits a suppressive activity at a similar level to α-tocopherol, while hydrangenol exhibits a weak suppressive activity thereto [Natural Medicine, 49(1), 84(1995)].
In regard to anti-bacterial activity, it is reported that phyllodulcin at 1000 ppm exhibits a proliferation suppressive activity on Staphylococcus aureus and Staphylococcus epidemidis (Japanese Published Unexamined Patent Application No. 43460/93), and phyllodulcin and hydrangenol exhibit an anti-bacterial activity on Bacteroides melaninogenicus and Fusobacterium nucleatum with the minimum growth inhibitory concentration of 1.25-2.5 ppm (Japanese Published Unexamined Patent Application No. 92829/94).
In regard to differentiation-inducing activity on leukocyte [Chemical & Pharmaceutical Bulletin, 48(4), 566 (2000)], isocoumarins such as thunberginol A (active at 100 μM) are reported to have more potent activity in vitro than dihydroisocoumarin such as phyllodulcin or hydrangenol (active at 300 μM). In addition, hydrangenol is reported to have a hyaluronidase inhibitory activity [Planta Medica, 54, 385 (1988)].
Moreover, it is reported that the extract of Hydrangeae Dulcis Folium (500 mg/kg) exhibits a cholagogic activity in an in vitro test, however, phyllodulcin (200 mg/kg) and hydrangenol (200 mg/kg) do not exhibit this activity [Journal of the Pharmaceutical Society of Japan, 114(6), 401 (1994)].
Furthermore, it is reported that the extract of Hydrangeae Dulcis Folium (200 and 400 mg/kg, oral administration) suppresses rat gastric ulcer induced by ethanol hydrochloride, however, phyllodulcin (75 mg/kg, oral administration) and hydrangenol (75 mg/kg, oral administration) do not suppress the ulcer [Journal of the Pharmaceutical Society of Japan, 114(6), 401 (1994)]